1. Field of the Invention
The present invention relates to a positively charged drug carrier which forms a complex with a negatively charged drug. More specifically, the present invention relates to a positively charged polymeric micelle type drug carrier which comprises an A-B block type copolymer wherein A is a hydrophilic polymer block and B is a hydrophobic biodegradable polymer block and wherein one end of the hydrophobic polymer block (B) is covalently bound to one cationic group. The positively charged biodegradable block copolymer of the present invention forms a complex with a negatively charged drug via electrostatic interactions. The cationic copolymers of the present invention can be used in drug delivery and are especially useful for delivery of anionic bioactive agents.
2. Related Art
Biodegradable polymers are gaining attention as drug delivery systems. R. Langer, New Methods of Drug Delivery, 249 Science 1527–1533 (1990); B. Jeong et al., Biodegradable Block Copolymers as Injectable Drug-delivery Systems, 388 Nature 860–862 (1997). Delivering bioactive agents from biodegradable delivery systems is very desirable because the need for surgery to remove the delivery system is avoided. Controlled release of bioactive agents can reduce the required frequency of administration by maintaining adequate concentration of the therapeutic agent. One important means of maintaining a proper concentration is to control the degradation rate of the biodegradable drug delivery system.
The biodegradable hydrophobic polymers that are widely used as drug carriers include polylactic acid (PLA), polyglycolic acid (PGA), a copolymer of lactic acid and glycolic acid (PLGA), polycaprolactone (PCL), polyorthoester (POE), polyamino acid (PAA), polyanhydride (PAH), polyphosphazine, polyhydroxybutyric acid (PHB), polydioxanone (PDO), etc. Such polymers have good biocompatibility and the desirable feature of being hydrolyzed and decomposed in a living body to give side products which have no toxicity. For these reasons, they are widely used as drug carriers. In particular, since these polymers are insoluble in water formulations, some drugs can be incorporated into the polymer matrix and then implanted in the body in the form of microspheres, nanospheres, films, sheets, or rods, whereby the drug is slowly released exerting a sustained therapeutic effect. In these types of formulations, the polymers themselves are finally decomposed in the body. However, these polymers have low affinity for water-soluble drugs making it very difficult to incorporate a large amount of drug into the polymer matrix. Even if the drug is effectively incorporated into the polymer matrix, the problem of an initial burst release (referring to the phenomenon whereby a large amount of drug is released within the first few hours) may occur after implantation into the body.
A-B, B-A-B, or A-B-A type block copolymers, wherein A is a hydrophilic polymer block and B is a hydrophobic biodegradable polymer block, have been used as drug carriers for the delivery of physiologically active materials in the form of polymeric micelles, nanospheres, microspheres, gels, etc. These block copolymers have desirable properties such as good biocompatibility and the ability to form core-shell type polymeric micelles in aqueous solutions where the core is composed of hydrophobic blocks and the shell is composed of hydrophilic blocks. Micellar formulations, wherein a poorly water soluble drug can be incorporated into the inside of polymeric micelle to give a micellar solution, are good drug carriers for hydrophobic drugs. However, since the drug is incorporated via hydrophobic interaction between the hydrophobic drugs and hydrophobic polymer, the incorporation efficiency of highly hydrophobic drugs is excellent, but water-soluble hydrophilic drugs are poorly incorporated into those polymeric micelles.
Kataoka et al. (EP 721,776 A1) have developed a method for incorporating a charged water-soluble drug into the inside of a polymeric micelle using a block copolymer consisting of a non-charged block and a charged block. The charged block used by Kataoka is a polyamino acid having an ionic side chain, such as polyaspartic acid, polyglutamic acid, polylysine, polyarginine, or polyhistidine. However, they are not biodegradable in a living body. In addition, since the charged block may include several functional groups having electric charges, when they are combined inside the microsphere via electrostatic binding with a drug having multiple ionic groups, such as peptides or proteins, they may decrease the stability of such drugs.
In view of the foregoing, development of a drug carrier for anionic drug delivery that is biocompatible and biodegradable will be appreciated and desired. Thus, the present invention provides a new type of positively charged amphiphilic block copolymer that is biocompatible and biodegradable and that can effectively deliver the drug without a decrease in its stability. By forming a complex with an anionic drug via electrostatic interaction, the cationic amphiphilic block copolymer of the present invention can effectively incorporate a water-soluble negatively charged drug into the amphiphilic block copolymer. In addition, the block copolymer of the present invention is readily susceptible to metabolic degradation after incorporation and delivery of the drug into the cell.